Single-agent maintenance poly(ADP-ribose) polymerase (PARP) inhibition may represent an effective strategy in patients with advanced/metastatic endometrial cancer responding to platinum-based chemotherapy, including for molecular subtypes with suboptimal options. To explore this approach, we initiated the randomized phase IIb UTOLA trial (NCT03745950). Female patients without progression following front-line platinum-based chemotherapy for advanced/metastatic endometrial cancer were randomized 2:1 to twice-daily maintenance oral olaparib 300 mg or placebo until progression or intolerance, stratified by p53 status, mismatch repair status, and response to initial chemotherapy. The primary endpoint was progression-free survival (PFS) in the intention-to-treat population. Secondary endpoints were PFS in subgroups, time to second progression or death, time to first and second subsequent therapy, objective response rate, overall survival, patient-reported outcomes, and safety. In the intention-to-treat population (n = 145), there was no PFS difference between olaparib and placebo (median 5.6 vs. 4.0 months, respectively; hazard ratio 0.94, 95% confidence interval 0.65–1.35; p = 0.74). However, intriguing numerical PFS effects were observed in exploratory analyses of pre-specified subgroups (p53-abnormal, complete response to initial chemotherapy, chromosomal instability). There was no overall survival difference between treatments. Grade 3/4 adverse events occurred in 36% versus 10% of olaparib- versus placebo-treated patients and were consistent with the olaparib safety profile in other cancers. Maintenance olaparib did not improve PFS, but promising numerical effects in subsets of patients warrant prospective evaluation.

Background: a specific subset of metastatic triple-negative breast cancers (mTNBC) is characterized by homologous recombination deficiency (HRD), leading to enhanced sensitivity to platinum-based chemotherapy. Apart from mutations in BRCA1/2 genes, the evaluation of other HRD-related alterations has been limited to date. As such, we analyzed data from mTNBC patients enrolled in the ProfiLER-01 study to determine the prevalence of alterations in homologous recombination-related (HRR) genes and their association with platinum sensitivity. Methods: next-generation sequencing and promoter methylation of BRCA1 and RAD51C were performed on tumors from patients with mTNBC, using a panel of 19 HRR genes. Tumors were separated into three groups based on their molecular status: mutations in BRCA1/2, mutations in other HRR genes (BRCA1/2 excluded) or BRCA1/RAD51C promoter methylation and the absence of molecular alterations in HRR genes (groups A, B and C, respectively). Sensitivity to platinum-based chemotherapy was evaluated through the radiological response. Results: mutations in BRCA1/2 were detected in seven (13.5%) patients, while alterations in other HRR genes or hypermethylation in BRCA1 or RAD51C were reported in 16 (30.7%) patients; furthermore, no alteration was found in the majority of patients (n = 29; 55.8%). Among 27 patients who received platinum-based chemotherapy, the disease control rate was 80%, 55% and 18% (groups A, B and C, respectively; p = 0.049). Regarding group B, patients with disease control exhibited mutations in FANCL, FANCA and the RAD51D genes or RAD51C methylation; Conclusion: mutations in HRR genes and epimutations in RAD51C were associated with disease control through platinum-based chemotherapy. As such, apart from well-characterized alterations in BRCA1/2, a more comprehensive evaluation of HRD should be considered in order to enlarge the selection of patients with mTNBC that could benefit from platinum-based chemotherapy.

Background: Maintenance niraparib at an individualized starting dose (ISD) is established in platinum-sensitive recurrent ovarian cancer (PSROC). However, patients’ perspectives on the burden of prolonged maintenance therapy have not been reported in prospective trials or routine practice. Methods: In the real-life multicenter NiQoLe study, patients with PSROC received ISD maintenance niraparib. The primary objective was to describe physician-reported adverse events (AEs) leading to treatment modification during the first 3 months. Secondary endpoints included patient-reported outcomes (symptomatic AEs using PRO-CTCAE, self-reported fatigue, and impact on daily activities/function using FACT-F) collected remotely weekly using a specifically designed electronic device. Results: Most (80%) of 139 treated patients (median age = 70 years) began niraparib at 200 mg/day. Median treatment duration was 5.7 (range = 0.2-21.4) months. During the first 3 months, 86 patients (62%) required treatment modification (median = 27 days to modification). Physician-reported grade ≥3 niraparib-related AEs occurred in 34 patients (24%); 68 patients (49%) had treatment modification for AEs, predominantly thrombocytopenia. The most frequent patient-reported AEs (PRO-CTCAE) were fatigue, insomnia, constipation, and dry mouth. Self-reported AEs were severe in 66% of patients. At baseline, 33% of patients reported severe fatigue (FACT-F), which generally persisted during niraparib. Physicians systematically underestimated major patient-reported symptoms. Conclusions: In routine practice, niraparib dose modification was often required during the first 3 months despite individualized dosing. Physicians underestimated the burden of fatigue and symptomatic AEs. Digital self-reporting of AEs is feasible, provides patient-centered information complementing physician-reported AEs, and allows fuller appreciation of toxicity in real-world studies. Clinical trial information: NCT03752216

Purpose: Aromatase inhibitors (AI) are used to treat estrogen receptor (ER)–positive low-grade endometrioid endometrial cancer. In breast cancer, ESR1 mutations are rare at diagnosis (<5%) but are frequently acquired in AI-resistant cases and are considered one of the major resistance mechanisms to endocrine therapy. This study aimed to assess the prevalence of ESR1 mutations in hormonotherapy-naïve endometrial cancer samples and correlate them with molecular profiles, ER expression, and clinical outcomes. Experimental Design: A total of 147 patients with advanced endometrial cancer who had responded to first-line chemotherapy were recruited into the UTOLA trial. Archival endometrial cancer tumor tissues underwent sequencing of 127 genes, including ESR1. Only hotspot mutations in the ligand-binding domain were evaluated. ESR1 mutation prevalence was validated in the Genomics England dataset. In UTOLA, tumors were classified as POLE, MMR deficient, TP53abn, or no specific molecular profiles (NSMP) based on the Proactive Molecular Risk Classifier for Endometrial Cancer (PROMISE) classification. Results: Of 147 patients, 137 had sufficient tumor material for sequencing. ESR1 mutations were identified in eight tumors (6%), including Y537S/C/N (n = 4), L536H/P (n = 2), and E380Q (n = 2). A similar prevalence (3.5%) was found among 1,311 tumors in the Genomics England dataset. All ESR1 mutation cases were low-grade endometrioid endometrial cancer, ER-positive, and PR-positive, and classified as NSMP. Among patients with metastatic NSMP low-grade endometrioid endometrial cancer, 22% (8/37) harbored ESR1 mutations. Survival outcomes after platinum chemotherapy were similar between patients with ESR1 mutation endometrial cancer and ESR1 wild type (median, not reached vs. 25.3 months; P = 0.114). Conclusions: ESR1 mutations, while rare overall in treatment-naïve endometrial cancer, are more prevalent in patients with NSMP low-grade endometrioid endometrial cancer, potentially affecting AI efficacy. ESR1 status should be considered in selecting hormonotherapy and as a stratification factor in AI trials.

Background: QUALIOR-phase 2 multicenter trial explored the feasibility of a home-based supervised physical exercise program (SPEP) in metastatic cancer patients receiving oral targeted therapies. Methods: Patients with metastatic cancers receiving oral targeted therapies were randomized (2:1) to a 3-month home-based SPEP (with a coach at home) or recommended adapted physical exercises (booklet). Primary endpoint was feasibility defined as the rate of patients who performed at least 50% of the theoretically planned sessions in the SPEP arm. Main secondary endpoints were fatigue and pain evaluated by visual analogue scales (VAS) during the program. Results: Among 112 patients, 74 and 38 were included in the SPEP and control arms, respectively. Median age was 59 (range: 31-83) years and the majority of patients were women. Main primary tumor location was breast (57%) and kidney (16%). Thirty-three (30%) patients were treated with anti–angiogenic tyrosine kinase inhibitors, and 53 (47%) received epidermal growth factor receptor or cell cycle inhibitors. Forty-five (61%) patients performed at least 50% of the SPEP. Median fatigue decreased from 4 to 3 (range: 0-10) after 3 months in the SPEP group with maintain of pain control. The percentage of patients with high level VAS of fatigue at 3 months was lower in SPEP arm than in the control arm (27% vs. 62%, P = .004). Conclusions: QUALIOR showed that SPEP with a coach at home was feasible in patients with metastatic cancers treated with oral targeted therapies. This program could mitigate the fatigue induced by oral targeted therapies.